|Publication number||US7547292 B2|
|Application number||US 10/466,076|
|Publication date||16 Jun 2009|
|Filing date||11 Jan 2002|
|Priority date||11 Jan 2001|
|Also published as||CA2433992A1, DE60210063D1, DE60210063T2, EP1365824A1, EP1365824B1, US20040215135, USRE43824, WO2002055139A1, WO2002055139A8|
|Publication number||10466076, 466076, PCT/2002/114, PCT/GB/2/000114, PCT/GB/2/00114, PCT/GB/2002/000114, PCT/GB/2002/00114, PCT/GB2/000114, PCT/GB2/00114, PCT/GB2000114, PCT/GB200114, PCT/GB2002/000114, PCT/GB2002/00114, PCT/GB2002000114, PCT/GB200200114, US 7547292 B2, US 7547292B2, US-B2-7547292, US7547292 B2, US7547292B2|
|Inventors||Colin David Sheldrake, George Costigan, Brian John Bellhouse|
|Original Assignee||Powderject Research Limited|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (102), Non-Patent Citations (1), Referenced by (60), Classifications (9), Legal Events (4)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This invention relates to needleless syringes for use in delivering particles into target tissue of a subject, for example skin or mucosa. Said particles may, for example, comprise a drug, vaccine, diagnostic agent or carrier particle coated with a genetic material (or any combination thereof).
The ability to deliver pharmaceuticals through skin surfaces (transdermal delivery) provides many advantages over oral or parenteral delivery techniques. In particular, transdermal delivery provides a safe, convenient and noninvasive alternative to traditional drug administration systems, conveniently avoiding the major problems associated with oral delivery (e.g. variable rates of absorption and metabolism, gastrointestinal irritation and/or bitter or unpleasant drug tastes) or parenteral delivery (e.g. needle pain, the risk of introducing infection to treated individuals, the risk of contamination or infection of health care workers caused by accidental needle-sticks and the disposal of used needles). In addition, transdermal delivery affords a high degree of control over blood concentrations of administered pharmaceuticals.
A novel transdermal drug delivery system that entails the use of a needleless syringe to fire powders (i.e. solid drug-containing particles) in controlled doses into and through intact skin has been described. In particular, U.S. Pat. No. 5,630,796 to Bellhouse et al. describes a needleless syringe that delivers pharmaceutical particles entrained in a supersonic gas flow. The needleless syringe is used for transdermal delivery of powdered drug compounds and compositions, for delivery of genetic material into living cells (e.g. gene therapy) and for the delivery of biopharmaceuticals to skin, muscle, blood or lymph. The needleless syringe can also be used in conjunction with surgery to deliver drugs and biologics to organ surfaces, solid tumours and/or to surgical cavities (e.g. tumour beds or cavities after tumour resection). In theory, practically any pharmaceutical agent that can be prepared in a substantially solid, particulate form can be safely and easily delivered using such devices.
One needleless syringe described in U.S. Pat. No. 5,630,796 comprises an elongate tubular converging-diverging nozzle having a rupturable membrane initially closing the passage through the nozzle and arranged substantially adjacent to the upstream end of the nozzle. Particles of a therapeutic agent to be delivered are disposed adjacent to the rupturable membrane and are delivered using an energizing means which applies a gaseous pressure to the upstream side of the membrane sufficient to burst the membrane and produce a supersonic gas flow (containing the pharmaceutical particles) through the nozzle for delivery from the downstream end thereof. The particles can thus be delivered from the needleless syringe at very high velocities which are readily obtainable upon the bursting of the rupturable membrane. The passage through the nozzle has an upstream convergent portion, leading through a throat to a downstream, divergent portion. The converging-diverging passage is used to accelerate the gas to supersonic speed. The gas is first brought to Mach 1 in the throat and the downstream divergence accelerates it to a steady state supersonic speed.
With the syringes described in U.S. Pat. No. 5,630,796 particles can be delivered at a large range of velocities with potentially non-uniform spatial distribution across the target surface. A variation in particle velocity can make it difficult to deliver high-potency powdered drugs, vaccines etc to specific target layers within the skin. Furthermore, non-uniform spatial distribution can cause problems which would be ameliorated if a more even spatial distribution could be achieved. In addition, flow considerations inside the syringes can limit the maximum size of the target area on the target tissue over which the particles may be spread, limiting the maximum particle payload size.
Additionally, with the syringes described in U.S. Pat. No. 5,630,796 the bursting of the rupturable membrane can make operation of the syringe fairly noisy, which can be a disadvantage when treating small children for example.
It would be advantageous to have a needless syringe which operates quietly and in which the particles may be spread over a larger target area, with a reasonably uniform distribution over that target area. By spreading the particles of the payload over a larger target area, with good uniformity of particle distribution over that target area, larger payloads may be delivered.
According to a first aspect of the present invention there is provided a method of distributing particles in a flow of gas from a needleless syringe, the method comprising:
(a) flowing gas through a first convergence in a gas flow path within the syringe thereby expanding the gas and reducing its pressure to provide a region of reduced gas pressure;
(b) utilizing said reduced gas pressure to draw a payload of particles into said gas flow path from outside of said gas flow path and to entrain them in the gas flow in said gas flow path; and
(c) directing the gas through a delivery nozzle bounding said gas flow path so as to accelerate the entrained particles and cause the entrained particles to be distributed across substantially the full width of the nozzle at the nozzle's downstream exit.
By distributing the particles in the flow of gas from a needleless syringe using the method of the above first aspect of the present invention, whilst the nozzle's downstream exit is positioned adjacent a target area of skin or mucosa, the particles may be administered to the skin or mucosa.
According to a second aspect of the present invention there is provided a needleless syringe for use in the needleless injection of particles into the tissue of a vertebrate subject, the syringe comprising:
The use of a reduced pressure to draw particles into the gas flow path allows the membranes which were previously used to retain the particles to be dispensed with. This in turn ensures that the device works more quietly since the noise created by the bursting of the membrane is no longer present.
Preferably, the device is so constructed and arranged that substantial boundary layer separation between the wall of the nozzle and the gas jet is avoided thus enabling the particles accelerated out of the exit nozzle in the gas jet to be distributed across substantially the full width of the nozzle's downstream exit.
By avoiding substantial boundary layer separation of the gas jet from the nozzle wall, the particles being accelerated can be distributed across substantially the full cross-section of the nozzle at the nozzle's downstream exit. Where the nozzle has a divergent downstream section, it has been found that by extending the length of the nozzle to increase the diameter of the nozzle at its downstream exit, significantly larger target areas on the skin or mucosa may be penetrated by the particles, with good uniformity of distribution across the larger target area.
According to a third aspect of the present invention there is provided a method of creating a gas flow in a needleless syringe, said method comprising:
The use of two convergences in this manner has been found to be a particularly advantageous way of creating a gas flow field suitable for accelerating particles in a needleless syringe.
Embodiments of apparatus in accordance with the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which:
Before describing the present invention in detail, it is to be understood that this invention is not limited to particular pharmaceutical formulations or process parameters as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting.
All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.
It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a therapeutic agent” includes a mixture of two or more such agents, reference to “a gas” includes mixtures of two or more gases, and the like.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.
The following terms are intended to be defined as indicated below.
The term “needleless syringe,” as used herein, expressly refers to a particle delivery system that can be used to deliver particles into and/or across tissue, wherein the particles may have an average size ranging from about 0.1 to 250 μm, preferably about 1-70 μm, more preferably 10-70 μm. Particles larger than about 250 μm can also be delivered from these devices, with the upper limitation being the point at which the size of the particles would cause untoward pain and/or damage to the target tissue. The particles may be delivered at high velocity, for example at velocities of at least about 150 m/s or more, and more typically at velocities of about 250-300 m/s or greater. Such needleless syringes were first described in commonly-owned U.S. Pat. No. 5,630,796 to Bellhouse et al., incorporated herein by reference, and have since been described in commonly owned International Publication Nos. WO 96/04947, WO 96/12513, and WO 96/20022, all of which publications are also incorporated herein by reference. These devices can be used in the transdermal delivery of a therapeutic agent into target skin or mucosal tissue, either in vitro or in vivo (in situ); or the devices can be used in the transdermal delivery of generally inert particles for the purpose of non- or minimally invasive sampling of an analyte from a biological system. Since the term only relates to devices which are suitable for delivery of particulate materials, devices such as liquid-jet injectors are expressly excluded from the definition of a “needleless syringe.”
The term “transdermal” delivery captures intradermal, transdermal (or “percutaneous”) and transmucosal administration, i.e., delivery by passage of a therapeutic agent into and/or through skin or mucosal tissue. See, e.g., Transdermal Drug Delivery: Developmental Issues and Research Initiatives, Hadgraft and Guy (eds.), Marcel Dekker, Inc., (1989); Controlled Drug Delivery: Fundamentals and Applications, Robinson and Lee (eds.), Marcel Dekker Inc., (1987); and Transdermal Delivery of Drugs, Vols. 1-3, Kydonieus and Berner (eds.), CRC Press, (1987). Aspects of the invention which are described herein in the context of “transdermal” delivery, unless otherwise specified, are meant to apply to intradermal, transdermal and transmucosal delivery. That is, the present invention, unless explicitly stated otherwise, should be presumed to be equally applicable to intradermal, transdermal and transmucosal modes of delivery.
As used herein, the terms “therapeutic agent” and/or “particles of a therapeutic agent” intend any compound or composition of matter which, when administered to an organism (human or animal) induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, biological response modifiers, nucleic acids, gene constructs and the like. More particularly, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants, anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; local and general anesthetics; anorexics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antigens, antihistamines; anti-inflammatory agents; antinauseants; antineoplastics; antipruritics; antipsychotics; antipyretics; antispasmodics; cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics); antihypertensives; diuretics; vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins peptides and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like).
Particles of a therapeutic agent, alone or in combination with other drugs or agents, are typically prepared as pharmaceutical compositions which can contain one or more added materials such as carriers, vehicles, and/or excipients. “Carriers,” “vehicles” and “excipients” generally refer to substantially inert materials which are nontoxic and do not interact with other components of the composition in a deleterious manner. These materials can be used to increase the amount of solids in particulate pharmaceutical compositions. Examples of suitable carriers include water, silicone, gelatin, waxes, and like materials. Examples of normally employed “excipients,” include pharmaceutical grades of dextrose, sucrose, lactose, trehalose, mannitol, sorbitol, inositol, dextran, starch, cellulose, sodium or calcium phosphates, calcium sulfate, citric acid, tartaric acid, glycine, high molecular weight polyethylene glycols (PEG), and combinations thereof. In addition, it may be desirable to include a charged lipid and/or detergent in the pharmaceutical compositions. Such materials can be used as stabilizers, anti-oxidants, or used to reduce the possibility of local irritation at the site of administration. Suitable charged lipids include, without limitation, phosphatidylcholines (lecithin), and the like. Detergents will typically be a nonionic, anionic, cationic or amphoteric surfactant. Examples of suitable surfactants include, for example, Tergitol® and Triton® surfactants (Union Carbide Chemicals and Plastics, Danbury, Conn.), polyoxyethylenesorbitans, e.g., TWEEN® surfactants (Atlas Chemical Industries, Wilmington, Del.), polyoxyethylene ethers, e.g., Brij, pharmaceutically acceptable fatty acid esters, e.g., lauryl sulfate and salts thereof (SDS), and like materials.
The term “analyte” is used herein in its broadest sense to denote any specific substance or component that one desires to detect and/or measure in a physical, chemical, biochemical, electrochemical, photochemical, spectrophotometric, polarimetric, colorimetric, or radiometric analysis. A detectable signal can be obtained, either directly or indirectly, from such a material. In some applications, the analyte is a physiological analyte of interest (e.g., a physiologically active material), for example glucose, or a chemical that has a physiological action, for example a drug or pharmacological agent.
As used herein, the term “sampling” means extraction of a substance, typically an analyte, from any biological system across a membrane, generally across skin or tissue.
Fitted generally midway along the central aperture of the main body 1 is a sonic nozzle 4. This sonic nozzle 4 is provided with an aperture which forms a first convergence or constriction 5 to the flow of gas through the main body 1. In this embodiment, the first convergence takes the form of two successive fairly abrupt constrictions 5 a, 5 b. The aperture of the first convergence is coaxial with the central longitudinal axis of the bore 3 of the nozzle 2.
The portion of the sonic nozzle 4 forming the downstream end of the constriction 5 b projects outwardly (in a downstream direction) from the flat main downstream face 6 of the sonic nozzle 4. Although not shown, the sonic nozzle 4 may be held in place within the central aperture of the main body 1 by cooperating screwthreads, or an interference fit in combination with a downstream shoulder formed by the main body 1.
It will be noted that the flat, main downstream face 6 of the sonic nozzle 4 is spaced upstream from the upstream face 7 of nozzle 2. The two faces 6, 7, in combination with the central aperture of the main body 1 between those two faces 6, 7, define a chamber 8 for particle entrainment.
The upstream end of the nozzle 2 forms a second convergence or constriction 9 to the flow of gas through the main body 1. Again, in this embodiment, this convergence 9 is a fairly abrupt constriction. The nozzle 2 bounds the gas flow path, that is to say it surrounds and defines the space through which the gas may flow.
The sonic nozzle constriction 5 b has a significantly reduced flow cross-section relative to the flow cross-section of the particle entrainment chamber 8. Similarly, the second convergence 9 has a much reduced flow cross-section relative to the flow cross-section of the chamber 8. In the illustrated embodiment, the nozzle 2 is 50 mm in length, the diameter of the sonic nozzle constriction 5 b is 1 mm and the diameter of the exit nozzle constriction 9 is 2.3 mm. In contrast, the diameter of the particle entrainment chamber 8 is 5 mm. Consequently, the flow cross-section of the second convergence 9 is approximately 5.3 times larger than the flow cross-section of the first convergence 5. The ratio of flow cross-sections between the first and second convergences 5, 9 is relevant to the functioning of the syringe.
A particle inlet in the form of a particle inlet passage 10 is provided extending radially through the main body 1. The radially innermost end of the particle inlet passage 10 opens into the particle entrainment chamber 8 and the radially outer end of the passage 10 is arranged to communicate with a particle source 11 containing a payload of particles.
As can be seen from
In the embodiment illustrated in
In order to operate the syringe illustrated in
In use, in order to operate the needleless syringe, a known volume of gas at a known pressure is suddenly released from the gas source (not shown) into the central aperture of the main body to the upstream side of the sonic nozzle 4. The initial pressure is sufficiently high so as to establish choked flow of the gas at the exit of the sonic nozzle 4, at its smallest constriction 5 b. The transsonic gas jet which issues from the constriction 5 b into the particle entrainment chamber 8 expands to create a reduced pressure region in the particle entrainment chamber 8, in a manner similar to the venturi effect. The reduced pressure region is sub-atmospheric in this embodiment. It is this sub-atmospheric pressure region in cooperation with the atmospheric pressure in the particle source 11, which draws a payload of particles from the reservoir 12 of the particle source 11 into the chamber 8, along the particle inlet passage 10, and in so doing causes the drawn-in particles to become mixed and entrained in the expanding gas jet in the particle entrainment chamber 8.
As with all embodiments, helium is preferably used as the driver gas. However, the gas issuing from the device is actually a mixture of helium and air, due to the air that is drawn in along with the particles via the particle inlet passage 10. Typically, the gas comprises about 15% air (by mass) at exit (the rest being helium).
The relative sizes of the first and second convergences 5,9, as well as the longitudinal spacing therebetween, is such as to encourage the expanding, diverging gas jet to attach to the walls of the second convergence 9 and to remain attached to the walls of the nozzle 2 as the jet passes down the bore 3 of the nozzle 2. The radius of the chamber 8 is not thought to be particularly important although it should be large enough so that a free jet is capable of being formed in the chamber. By remaining attached, and thus avoiding substantial boundary layer separation of the gas jet from the walls of the second convergence 9 and the nozzle bore 3, the particles entrained in the gas jet are distributed across substantially the full cross-section of the nozzle bore 3. In this way, when the gas jet, with particles entrained therein, exits the nozzle's downstream exit and impacts a target area of tissue (eg. skin or mucosa) positioned in close proximity to the nozzle exit, the size of the target area impacted by the particles will be generally equal to the size of the bore 3 at the downstream exit of the nozzle 2 and the particles will be well distributed across the target area. By avoiding the formation of a substantial concentration of the particles within the core of the target area with no or few particles around the boundary of the target area, increased payloads of particles may be delivered without the central core of the target area becoming overloaded with particles.
When a syringe similar to that illustrated in
Comparable performance was achieved with a canister containing helium at a pressure of 20 bar. When used with the 2.3 mm nozzle bore exit diameter syringe illustrated in
Performance comparisons (of which more later) between the different embodiments were made by discharging the embodiment of device, loaded with a known payload (between 1 mg and 3 mg) of 48 μm diameter polystyrene spheres above a 3% agar gel target. Vented spacers were fitted to the end of the device nozzle so as to keep the devices at a fixed distance from the target surface and at right angles to it. After firing off the syringe the agar was then photographed to record the delivery footprint. The gel target was then sliced across its diameter and thin sections were photographed through a microscope to establish the depth of penetration of the individual particles.
Although the anaesthetic performance of the
The length of the upstream parallel-sided section 16 of the bore of the nozzle 15 is 7 mm. After the upstream parallel-sided section 16, the divergent downstream section 17 has a cone angle of approximately 8.8° and diverges to provide the bore of the nozzle 15 with a 10 mm exit diameter at the nozzle's downstream exit 19.
The divergent section 17 is thought to allow the jet issuing from the sonic nozzle 4 to continue to expand supersonically before being broken down by a series of oblique shocks.
When the syringe of
As with the first embodiment, with the second embodiment it is thought that the good distribution of particles across a target area substantially equal to the size of the nozzle at the nozzle's downstream exit is influenced by the relative minimum sizes of the first and second convergences 5, 16, the distance by which they are spaced apart and the positioning of the particle inlet passage 10 relative to the exit of the first convergence and the entrance to the second convergence. In the second embodiment, it is thought also to be advantageous to have an upstream parallel-sided section 16 ahead of the divergent downstream section 17, as it is thought that the parallel-sided section 16 assists in settling down the gas flow and reattaching to the nozzle walls the diverging gas jet emanating from the first convergence 5.
A small scale clinical trial was conducted with the first and second embodiments of the syringe to test their efficacy when delivering lidocaine to the human skin.
Five volunteers had 1.5 mg of lidocaine administered to their volar forearms. After three minutes, two needle probes were used to compare the pain experienced at the treated site with that at an untreated site close by. All but one of the volunteers found that the needle probes at the active sites were less painful than those at the non-active sites. Subsequently two volunteers tested lidocaine administrations to the fossa. Both found that the treated sites were completely pain free.
The first embodiment of syringe appeared to be more effective over a small area of forearm than the second embodiment of syringe used with the same particle payload. Because, however, the particle penetration depth was similar in both cases a likely explanation for this is that insufficient lidocaine particles were being administered to the 10 mm diameter target area with the second embodiment of syringe.
The second embodiment of syringe was also modified by extending its nozzle 15 in length. By maintaining the same taper angle of 8.8 degrees, the diameter of the nozzle at its downstream exit 19 was increased to 14 mm from 10 mm. This modified arrangement was tested with a 3 mg payload of lidacaine powder using a 5 ml cylinder of helium at 30 bar. The results are shown in
The first and second embodiments described above utilize a first convergence or constriction 5 to create a reduced pressure region which is used to draw in a payload of particles. The first convergence or constriction as described comprises an upstream constriction 5 a and a downstream constriction 5 b. It is the smaller downstream constriction 5 b that is choked during use. The third embodiment relates to a modification of this geometry which replaces the two-stage convergence of the first and second embodiments with a smoothly tapering convergence 5′. As shown in
The chamber 8 is the preferred position for the particle inlet passage 10 (not shown in
The third embodiment works in a very similar way to the first and second embodiments in so far as there is provided a first convergence or constriction followed by a chamber of increased cross-section followed by another convergence or constriction. The chamber of increased cross-section is thought to provide a discontinuity to the gas flow which leads to the creation within the chamber of a transsonic jet, which jet passes through the chamber and attaches to the walls of the nozzle bore 3 in the region of the second convergence 9. As the transsonic jet enters the second convergence, a normal shock wave is thought to be formed across the second convergence which increases the pressure and reduces the velocity of the gas. The nozzle portion then serves to accelerate the particles in the already quickly moving gas stream.
As already mentioned, the first and third embodiments (with a parallel sided nozzle bore 3) are thought to have particular application in dentistry where it is useful to achieve penetration of a small target area and where the mucosal surfaces are relatively easy to penetrate. This in turn means that low driving pressures can be used (i.e. the pressure presented to the first convergence 5), such as 10 bar for example. It has been found that the lower the driving pressure, the less noise that is created by the device.
In all embodiments, the mass flow rate of gas through the device is determined by the driver pressure and the smallest cross sectional flow area in the device. This smallest area is preferably the first convergence 5, 5′. Thus, it is expected that the first convergence will be choked during normal operation.
As in the first to fourth embodiments, the particle source 37 takes the form of a cassette having a reservoir 38 provided therein to receive the payload of particles. This reservoir 38 is in communication with the particle entrainment chamber 39 via the particle inlet passage 40.
Provided at the upstream end of the particle entrainment chamber 39 is a sonic nozzle 41, whose central aperture forms the first convergence or constriction 42 to the flow of gas from the gas source. The second convergence or constriction 43 is provided by the upstream end of the upstream parallel-sided section 32 of the bore of the nozzle 31. The minimum diameters of the first and second convergences shown are 1 mm and 2.3 mm respectively.
The gas source is positioned to the left (as drawn) of the main body 30. The gas source includes a gas cylinder 44 received within a housing 45. The right-hand end (as drawn) of the gas cylinder 44 is provided with a longitudinally extending nose 49, which nose is capable of being fractured, so as to allow the escape of gas from the interior of the cylinder 44, upon the application of lateral pressure to the nose 45 in the direction identified by the arrow referenced 46. In the illustrated embodiment, this lateral pressure is applied by moving a plunger 47 radially inwardly, using the pressure from a thumb or finger, sufficiently far as to fracture the nose 49 and to cause gas release from the cylinder 44. It is this release of gas which pressurizes the space upstream of the sonic nozzle 41, leading to choked flow of the released gas through the first convergence 42.
The gas cylinder 44 need not have its nose pointed to the right (as drawn). It may, for example, be turned through 180° so that its nose points to the left.
So as to avoid the possibility of any fragments from the fracturing of the nose either blocking the sonic nozzle 41, or passing through the aperture provided in the sonic nozzle 41, a thin gauze filter 48 may, as shown, be provided between the gas cylinder 44 and the sonic nozzle 41 so as to filter the gas from the cylinder prior to its passage through the sonic nozzle 41.
The method and mechanism of operation of the fifth embodiment is similar to that of the first to fourth embodiments and will not be further described here.
In all the embodiments, the relationship between the area of the first and second convergences (or the relationship between the area of the first convergence and the area of the nozzle in the fourth embodiment) is thought to be significant. Diameters of 1.0 and 2.3 mm for the first and second convergences respectively, equating to a flow cross-sectional area ratio of 1:5.3 worked well. Other constructions that worked well were diameters of 1.2 and 3.0 mm for the first and second convergences, 1.3 and 3 mm for the first and second convergences and 1.4 and 3.5 mm for the first and second convergences respectively, equating to flow cross-sectional area ratios of 1:6.25, 1:5.3 and 1:6.25 respectively. In contrast, diameters of 1.2 and 2.3 for the first and second convergences respectively, equating to a ratio of 1:3.7 did not work well.
For the larger diameter first convergence (e.g. 1.4 mm), a larger mass flow rate can be established and a more powerful device can be constructed. Pressures of up to 60 bar may be used as a driver, in order to provide enough propellent to support the increased mass flow rate.
In the illustrated embodiments, the particle source 11, whilst suitable for use in the laboratory, would not be particularly well suited to commercial use because the powder to be delivered could become contaminated and/or fall out of the reservoir provided in the particle source cassette.
The cassette body 51 has three radial holes 53, 54 provided therein. Hole 54 is a single filling hole to enable the powder cavity 55 in the plug 52 to be filled with a metered dose of powder. A pair of diametrically opposed holes 53 are also provided, of which only one is visible in
It will be appreciated that there will be numerous other possible ways for hermetically sealing a pre-measured dose of powder prior to use of the syringe.
Various configurations of exit nozzle have been found to be effective.
To address this problem of “coring”, the nozzle shown in
The above embodiments all utilize a first convergence 5, 5′ to create a reduced pressure region which can be used to draw the particles into the gas flow path. In the embodiments shown, since the particles are initially provided in contact with the atmosphere, the reduced pressure must necessarily be sub-atmospheric for the effect to work properly. The seventh embodiment relates to a construction in which the particles are provided in fluid communication with an upstream portion of the gas flow path such that, in use, the reduced pressure need not be sub-atmospheric and need only be reduced compared to the pressure at that upstream portion of the flow path.
The amount of gas which flows along the passage 69 is preferably small compared to the flow rate along the gas flow path, e.g. 20% or so.
Theoretically, gas pressure close to the driver pressure can be used to inject the particles into the gas flow. Typically, though, the particle inlet passage 10 and passage 69 are positioned so that about 0.2 times the driver pressure is present across the particles in use. When 30 bar driver pressure is used, this corresponds to a pressure difference of 6 bar which serves to draw the particles into the flow. By modifying this pressure difference, the time at which the particles are drawn into the flow can be controlled. This timing can also be controlled by modifying the length and/or tortuousness of the passage 69.
Thus, this embodiment provides a form of particle “injection” and gives greater flexibility as to where the particles can be introduced since the requirement for sub-atmospheric pressure is dispensed with. Although the particles are shown being injected into the first convergence 5′, they may be injected into the chamber 8, the second convergence 9, the nozzle bore 3, 16, 17 or the divergent section 60 as described in relation to the other embodiments.
This embodiment has the further advantage that no atmospheric air is induced into the gas flow meaning that the device is self-contained in use. This reduces the possibility of contamination of the particles by contaminants suspended in atmospheric air.
As described above, a large divergent portion 17 of the exit nozzle 2 can cause “coring” whereby the boundary layer separates from the nozzle walls and the majority of the jet power is concentrated along a central longitudinal axis such that the particles are not evenly distributed across the full area of the nozzle at the nozzle exit plane. This can be ameliorated by the use of a second parallel section 65 (see
This embodiment utilizes a further nozzle geometry which is similar to the geometry shown in
The device shown in
Mass flow rates (and particle penetration) were also increased by using larger diameter sonic throats. In this embodiment, which utilizes the outside atmospheric pressure to draw in the particle payload, it is necessary to ensure that the sonic throat and parallel section of the diameters are matched, to prevent a blow-back of particles. The alignment of the sonic throat exit plane and the particle inlet passage 10 in the chamber 8 is also important in preventing the particle blow-back.
A 10 mm diameter exit plane device, fitted with a 1.2 mm diameter sonic throat and a 3 mm diameter upstream exit nozzle parallel section and using a 5 ml, 40 bar helium cannister gave the footprint and penetration results shown in
The left hand image shows the footprint (approximately 11 mm diameter) of the particles and a 3% agar gel target: there is an increased concentration of particles near the centre of the footprint, but the asymmetry of the distribution is not so noticeable in this image. The middle image shows the distribution of particles across a diametral slice of the target and the left hand image shows an enlarged view of particle penetration at the center of the slice, from which a maximum penetration of 250 μm can be measured.
Noise levels from this device at these conditions were not high (max=81 dBA, linear peak=120 dB, measured at 0.3 meters).
A simple silencer device (shown in
This arrangement produced significantly lower noise levels (max=73 dBA, linear peak=109 dB at 0.3 meters). Use of the silencer produces a back pressure which has two effects. The first effect is to generate a “lift-off” force which tends to separate the device from the target plane and the second effect is to reduce the performance of the device, since the gas is now expanded to a nozzle exit pressure above atmospheric.
The lift-off force of the silenced device was measured by operating it against a flat plate loaded with different masses, a displacement transducer indicating when the sealing force was insufficient to maintain contact. This method gave lift-off forces of the order of 5 N, which is considerably lower than the Fig. obtained by assuming that the peak pressure maintained on the plate generates the maximum lift-off force (13 N).
The device shown in
It can be seen from the Figures that the particles are fairly asymmetrically distributed on the target and that the distribution of penetration depths is large—ranging from 60 μm at the edges to 120 μm near the center.
A 30 mm parallel extension as shown in
An improved distribution and penetration was achieved by adding gold particles to larger diameter lidocaine powder in the powder cassette. The gold particles were sandwiched between two layers of lidocaine. The results are shown in
The most powerful version of the
It may be advantageous to provide a high efficiency particle air filter so as to remove any potential source of contamination from air drawn into the syringe through the cassette of the particle source. Such filters are commercially available and have low pressure drops. Such filters have an upper limit to gas velocity through the filter so as to ensure that they operate to the specification. The surface area of such a filter could clearly be chosen to match the gas velocity therethrough that will be encountered in use.
An alternative to an air filter would be to bleed a supply of driver gas at, or near, atmospheric pressure to the particle cassette inlet. As described above with relation to the seventh embodiment, however, the gas bled to the particle inlet may be substantially higher than atmospheric.
Although the above described embodiments were used for single dose operation, they may readily be modified to make them suitable for multiple dose operation, for example by providing them with a plurality of gas canisters and modifying the cassette of the particle source 11 to contain a plurality of discrete particle reservoirs 12, each of which can be indexed to align with the particle inlet passage 10 between successive shots.
Any of the already described nozzles may be contoured, for example, using the method of characteristics, to provide a reduction in the number of oblique shock waves that form in the nozzle during use. Profiling the nozzle in this way is also thought to improve the particle distribution at the exit plane.
For some use locations, such as surgeries, operating theaters and the like, in which connection of the syringe to a supply of gas using a flexible hose, for example, would be acceptable, multiple operation of the device could well be possible using a simple push-pull valve arrangement to fire the syringe.
The major components of the needleless syringe (main housing, sonic nozzle, nozzle barrel etc) may for example be made of metal or of engineering plastics materials. The latter materials are preferred because they may readily be molded and are light in weight.
Although the device of all embodiments of the present invention is designed to be quieter in operation than the device of U.S. Pat. No. 5,630,796 (which uses a rupturable membrane), some noise is still detected and a silencing device, perhaps comprising a plurality of baffles and a mesh filter can be used to further reduce the noise experienced.
The present invention is primarily concerned with the reduction of noise and improved uniform particle spread that can be achieved by using the Venturi effect to draw the particles into the gas flow path. However, the Venturi effect is not essential for this purpose and other methods of introducing the particles into the flow may be utilized. For example, the particles may be initially lightly adhered to the inside of a tubular member which is initially provided in the gas flow path. Upon actuation, the gas flow is able to shear the particles from the tube and thereby entrain them.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US4478368||11 Jun 1982||23 Oct 1984||Fluidyne Corporation||High velocity particulate containing fluid jet apparatus and process|
|US4555872||24 Jan 1984||3 Dec 1985||Fluidyne Corporation||High velocity particulate containing fluid jet process|
|US4586854||12 Jun 1985||6 May 1986||Nordson Corporation||Venturi powder pump having rotating diffuser|
|US4587772||6 Mar 1984||13 May 1986||National Research Development Corporation||Dispenser for a jet of liquid bearing particulate abrasive material|
|US4615649||5 Nov 1984||7 Oct 1986||Nordson Corporation||Powder pump having suction tube deflector|
|US4624080||13 Jan 1983||25 Nov 1986||Bilskade-Service Hb||Arrangement for use with blasting equipment|
|US4631871||18 Apr 1983||30 Dec 1986||Fluid Engineering Products Limited||Abrasive fluid jet apparatus|
|US4648215||7 Oct 1985||10 Mar 1987||Flow Industries, Inc.||Method and apparatus for forming a high velocity liquid abrasive jet|
|US4663893||16 Dec 1985||12 May 1987||The United States Of America As Represented By The Secretary Of The Interior||End deflector for abrasive water jet slot cutter|
|US4666083||21 Nov 1985||19 May 1987||Fluidyne Corporation||Process and apparatus for generating particulate containing fluid jets|
|US4668190||21 Oct 1985||26 May 1987||Overmyer Thad J||Liquid admixing apparatus for dental water-injection systems|
|US4674491||9 Aug 1985||23 Jun 1987||Inge Brugger||Inhaler|
|US4708214||22 Aug 1986||24 Nov 1987||The United States Of America As Represented By The Secretary Of The Interior||Rotatable end deflector for abrasive water jet drill|
|US4711056||12 Nov 1986||8 Dec 1987||Libbey-Owens-Ford Co.||Abrasive fluid jet radius edge cutting of glass|
|US4715535||28 Apr 1986||29 Dec 1987||Nordson Corporation||Powder spray gun|
|US4807814||3 Jan 1986||28 Feb 1989||Saint Gobain Vitrage||Pneumatic powder ejector|
|US4809706||13 Jan 1988||7 Mar 1989||Watson Robert L||Incentive inhalation spirometer apparatus|
|US4817874||31 Oct 1985||4 Apr 1989||Flow Systems, Inc.||Nozzle attachment for abrasive fluid-jet cutting systems|
|US4829724||11 Jan 1988||16 May 1989||Rohr Industries, Inc.||Cutting abrasive feeder, demand type|
|US4934111||9 Feb 1989||19 Jun 1990||Flow Research, Inc.||Apparatus for piercing brittle materials with high velocity abrasive-laden waterjets|
|US4941298||28 Sep 1988||17 Jul 1990||Mark Fernwood||Rear reservoir micro sandblaster|
|US4945688||22 Oct 1985||7 Aug 1990||Electric Power Research Institute, Inc.||Nozzle for entraining abrasive granules within a high pressure fluid jet and process of using same|
|US4951429||7 Apr 1989||28 Aug 1990||Flow Research, Inc.||Abrasivejet nozzle assembly for small hole drilling and thin kerf cutting|
|US5024656||30 Aug 1988||18 Jun 1991||Injet Medical Products, Inc.||Gas-pressure-regulated needleless injection system|
|US5037247||29 Nov 1989||6 Aug 1991||Nordson Corporation||Powder pump with internal valve|
|US5054249||23 Nov 1988||8 Oct 1991||Rankin George J||Method and apparatus for liquid-abrasive blast cleaning|
|US5155946||12 Jul 1991||20 Oct 1992||Gkss Forschungszentrum Geesthacht Gmbh||Method and apparatus for producing a water/abrasive mixture for cutting and cleaning objects and for the precise removal of material|
|US5283985||13 Apr 1993||8 Feb 1994||Browning James A||Extreme energy method for impacting abrasive particles against a surface to be treated|
|US5301878||2 Aug 1990||12 Apr 1994||The Victoria University Of Manchester||Device for producing a particulate dispersion|
|US5325638||15 Sep 1992||5 Jul 1994||Lynn William R||Pliant media blasting device|
|US5335459||27 Jul 1992||9 Aug 1994||Dale Brian D||Nozzle for abrasive cleaning or cutting|
|US5365762||8 Dec 1993||22 Nov 1994||General Electric Company||Suction-type shot peening machine sensor|
|US5366560||3 Sep 1993||22 Nov 1994||Yelapa Enterprises, Inc.||Cleaning method utilizing sodium bicarbonate particles|
|US5473947||11 Aug 1994||12 Dec 1995||Sames S. A.||Fluidized powder flowrate measurement method and device|
|US5505566||22 Jan 1993||9 Apr 1996||Wagner International Ag||Powder injector|
|US5514026||20 Oct 1993||7 May 1996||Sandair Nevada, Inc.||Unitary, hand-held, portable, self-powered refillable mixed-media ejector tool|
|US5533501||1 Jun 1994||9 Jul 1996||Medic-Aid Limited||Nebuliser|
|US5551909||28 Nov 1994||3 Sep 1996||Bailey; Donald C.||Method and apparatus for cleaning with high pressure liquid at low flow rates|
|US5571323||27 Mar 1995||5 Nov 1996||Nylok Fastener Corporation||Powder spray apparatus for the manufacture of coated fasteners|
|US5584807 *||20 Jan 1995||17 Dec 1996||Agracetus, Inc.||Gas driven gene delivery instrument|
|US5588901||31 Aug 1994||31 Dec 1996||Yelapa Corporation||Cleaning method and apparatus utilizing sodium bicarbonate particles|
|US5615980||7 Jun 1995||1 Apr 1997||Gema Volstatic Ag||Injector-feed device for pneumatic feed of powder|
|US5616067||16 Jan 1996||1 Apr 1997||Ford Motor Company||CO2 nozzle and method for cleaning pressure-sensitive surfaces|
|US5630796||7 Jun 1995||20 May 1997||Oxford Biosciences Limited||Method of delivering powder transdermally with needless injector|
|US5643058||11 Aug 1995||1 Jul 1997||Flow International Corporation||Abrasive fluid jet system|
|US5645380||18 Dec 1995||8 Jul 1997||Gema Volstatic Ag||Injector device for feeding coating powder|
|US5718581||9 May 1995||17 Feb 1998||Danville Manufacturing, Inc.||Air abrasive particle apparatus|
|US5749684||3 Jun 1996||12 May 1998||Fosfoquim S.A.||Particulate material feeding apparatus and process|
|US5860598||14 Aug 1997||19 Jan 1999||Cruz; Luis R||Fog atomizer|
|US5865796||16 Dec 1996||2 Feb 1999||Powderject Vaccines, Inc||Gas driven gene delivery instrument|
|US5873680||25 Jul 1997||23 Feb 1999||Elpatronic Ag||Method and injector arrangement for conveying pulverulent material|
|US5876267||15 Aug 1997||2 Mar 1999||Fuji Manufacturing Co., Ltd.||Blasting method and apparatus|
|US5906858||7 Aug 1996||25 May 1999||Elpatronic Ag||Method and apparatus for conveying a pulverulent material by means of an injector|
|US5951531||15 Apr 1994||14 Sep 1999||Medchem Products, Inc.||Apparatus and method for applying a particulate hemostatic agent to living tissue|
|US5954232||1 Aug 1996||21 Sep 1999||The Boc Group Plc||Gas delivery system|
|US5984677||9 May 1996||16 Nov 1999||Danville Engineering||Air abrasive particle apparatus|
|US5992772||25 Jun 1997||30 Nov 1999||Chem-Trend Incorporated||Apparatus for dispensing lubricating powder|
|US6012653||4 Oct 1997||11 Jan 2000||Sachsische Werkzeug Und Sondermaschinen||Modular abrasive medium water jet cutting head|
|US6040004||8 Mar 1996||21 Mar 2000||3M Innovative Properties Company||Method and apparatus for fabricating a particle-coated substrate, and such substrate|
|US6051274||28 Oct 1998||18 Apr 2000||Elpatronic Ag||Method for conveying pulverulent material|
|US6053889||13 Jun 1997||25 Apr 2000||Powderject Vaccines, Inc.||Sample delivery module for particle acceleration apparatus|
|US6093021||25 Jun 1997||25 Jul 2000||Rainey; J. Tim||Parallel air stream dental air-abrasion system|
|US6196269||1 Jun 1999||6 Mar 2001||Itw Gema Ag||Conveying injector|
|US6203186||13 Sep 1999||20 Mar 2001||Luis R. Cruz||Spherical eductor atomizer|
|US6217654||2 Nov 1998||17 Apr 2001||Itw Gema Ag||Method and equipment for powder spray coating|
|US6230703||2 Jun 1999||15 May 2001||Michael Bono||Aerosol inhalation device providing improved aerosol delivery|
|US6280302||24 Mar 1999||28 Aug 2001||Flow International Corporation||Method and apparatus for fluid jet formation|
|US20010003351||29 Dec 1998||14 Jun 2001||Patrick P. Chen||Dry particulate disperson system and flow control device therefor|
|US20010036801||26 Feb 2001||1 Nov 2001||Taylor Andrew M.||Method and apparatus for high pressure article cleaner|
|US20020000477||29 Jun 2001||3 Jan 2002||Shibuya Kogyo Co., Ltd||Cleaning nozzle and cleaning apparatus|
|CN1284383A||25 Aug 2000||21 Feb 2001||清华大学||Ejecting pneumatic gene accelerating microejection method and gene gun|
|DE3326602A1||23 Jul 1983||1 Mar 1984||Rohrleitungen Isolierungen Veb||Device for compressed-air blasting|
|DE3516103A1||4 May 1985||6 Nov 1986||Fraunhofer Ges Forschung||Mixing head for introducing abrasive particles into a high-pressure water jet|
|DE3531927A1||7 Sep 1985||12 Mar 1987||Ulmer Gmbh||Metal powder conveying device|
|DE3612473C2||14 Apr 1986||5 Oct 1989||Behindertenzentrum Stuttgart E.V., 7000 Stuttgart, De||Title not available|
|DE3634700A1||11 Oct 1986||14 Apr 1988||Ulrich Ebinger||Device for the sandblasting of small surface regions|
|DE3727441A1||17 Aug 1987||2 Mar 1989||Wassermann Dental Maschinen Gm||Dental sand blaster with pneumatically controlled sand treating unit|
|DE3805531A1||23 Feb 1988||31 Aug 1989||Intec Maschinenbau Gmbh||Method for conveying powder and apparatus for carrying out this method|
|DE4040227A1||15 Dec 1990||17 Jun 1992||Hans Georg Platsch||Dry powder aerosol generator - using dual air streams and having automatic powder recharging|
|DE4209353C2||23 Mar 1992||15 Dec 1994||Pro Aqua Geraete Gmbh||Feuchtstrahlanlage mit einer Strahlpistole|
|DE4313704C2||27 Apr 1993||18 May 1995||Fraunhofer Ges Forschung||Vorrichtung zum Erzeugen eines mit einem Abrasivmittel versetzten Flüssigkeitsstrahles|
|DE4322111C2||2 Jul 1993||10 May 2001||Pari Gmbh||Inhalationsvernebler|
|DE9307454U1||17 May 1993||21 Oct 1993||Rath Dieter||Strahldüse|
|DE10017556A1||3 Apr 2000||11 Oct 2001||Frank Heppes||Device for setting vacuum generated in one or more Venturi nozzles has baffle plate displaced linearly in fluid outlet region behind nozzle to set counter pressure|
|DE19541310A1||6 Nov 1995||7 May 1997||Suedmo Schleicher Ag||Apparatus for delivery of a dosed solid powder|
|DE19600450C2||9 Jan 1996||16 Apr 1998||Claus Dr Becker||Vorrichtung zum kontinuierlichen Abtragen von festen Materialien mit Hilfe von Fluidstrahlen|
|DE19729549A1||10 Jul 1997||14 Jan 1999||Kolb Robert Sen||Compressed air injector for pneumatically feeding powder|
|DE19804233A1||4 Feb 1998||12 Aug 1999||Kaercher Gmbh & Co Alfred||Strahlmittel-Injektorpistole|
|DE19807917A1||25 Feb 1998||26 Aug 1999||Air Liquide Gmbh||Jet stream of gas and dry ice particles for shot blast surface cleaning|
|DE19838276A1||22 Aug 1998||24 Feb 2000||Itw Gema Ag||Powder spray coating arrangement has variable choke control element in delivery airline whose flow resistance can be varied by control motor activated by electronic regulator|
|DE19961202C1||18 Dec 1999||26 Jul 2001||Daimler Chrysler Ag||Fixed inner spray nozzle to supply gas and powder mixture, for painting surfaces, has sleeve and insert, formed so that outer contour of insert forms Laval nozzle with inner contour of sleeve|
|DE20010854U1||19 Jun 2000||7 Sep 2000||Jou Wuu Cheau||Sandstrahlpistole|
|DE20106816U1||20 Apr 2001||19 Jul 2001||Schlick Heinrich Gmbh Co Kg||Strahlkopf|
|DE29603662U1||29 Feb 1996||20 Jun 1996||Kamphoff Horst Dipl Ing||Selbstzentrierende Mischkammer-Fokussierdüse zur Beschleunigung abrasiver Partikel|
|DE29905035U1||19 Mar 1999||10 Jun 1999||Mertik Maxitrol Gmbh & Co Kg||Gaskugelhahn|
|DE29923669U1||3 Apr 1999||12 Apr 2001||Bauer Erich||Kompaktes Pulverhandgerät mit neuem Stabinjektor, Reinigungsklammer und Injektorreinigungsgerät|
|EP0119338A1||17 Mar 1983||26 Sep 1984||Jetin Industrial Limited||High pressure liquid cutting apparatus|
|EP0445104A2||22 Feb 1991||4 Sep 1991||BÖHLER Gesellschaft m.b.H.||Method and device for entraining solid particles in a fluidic cutting stream|
|EP0458685B1||17 May 1991||27 Jul 1994||Total Raffinage Distribution S.A.||Process and device for the spraying of liquid, as well as their applications|
|EP0471323B1||12 Aug 1991||1 Dec 1999||PARI GmbH Spezialisten für effektive Inhalation||Atomizer for liquid medicaments|
|EP0525720A1 *||28 Jul 1992||3 Feb 1993||New England Pharmaceuticals, Inc.||Inhalation devices|
|WO1998022639A1 *||27 Oct 1997||28 May 1998||O.O.O. Obninsky Tsentr Poroshkovogo Napylenia||Apparatus for gas-dynamic coating|
|1||Yu Xinglong et al.: "Particle Acceleration for Delivery Deoxyribonucleic Acid Vaccine into Skin In Vivo", Review of Scientific Instruments, Aug. 2001, pp. 3390-3395, vol. 72, No. 8, American Institute of Physics.|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US8388569||19 Apr 2011||5 Mar 2013||Xerox Corporation||Delivery devices and methods with collimated gas stream and particle source|
|US8409376||2 Apr 2013||The Invention Science Fund I, Llc||Compositions and methods for surface abrasion with frozen particles|
|US8414356 *||9 Apr 2013||The Invention Science Fund I, Llc||Systems, devices, and methods for making or administering frozen particles|
|US8430839||30 Apr 2013||Palo Alto Research Center Incorporated||Drug delivery devices and methods with collimated gas stream and drug reservoir|
|US8485861||30 Oct 2009||16 Jul 2013||The Invention Science Fund I, Llc||Systems, devices, and methods for making or administering frozen particles|
|US8486002||19 Apr 2011||16 Jul 2013||Palo Alto Research Center Incorporated||Drug delivery devices and methods with collimated gas stream and release-activatable tape|
|US8518031||30 Oct 2009||27 Aug 2013||The Invention Science Fund I, Llc||Systems, devices and methods for making or administering frozen particles|
|US8540665||4 Nov 2009||24 Sep 2013||Powder Pharmaceuticals Inc.||Particle cassettes and processes therefor|
|US8545806||31 Mar 2009||1 Oct 2013||The Invention Science Fund I, Llc||Compositions and methods for biological remodeling with frozen particle compositions|
|US8545855||26 Feb 2009||1 Oct 2013||The Invention Science Fund I, Llc||Compositions and methods for surface abrasion with frozen particles|
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|US8568363||15 Sep 2009||29 Oct 2013||The Invention Science Fund I, Llc||Frozen compositions and methods for piercing a substrate|
|US8575132||11 Jan 2013||5 Nov 2013||Xin Ji||Modified starch material of biocompatible hemostasis|
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|US8721582 *||15 Jan 2010||13 May 2014||Xin Ji||Internal dry powder delivery system and method thereof|
|US8721583||31 Oct 2008||13 May 2014||The Invention Science Fund I, Llc||Compositions and methods for surface abrasion with frozen particles|
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|US8762067||31 Oct 2008||24 Jun 2014||The Invention Science Fund I, Llc||Methods and systems for ablation or abrasion with frozen particles and comparing tissue surface ablation or abrasion data to clinical outcome data|
|US8784384||15 Sep 2009||22 Jul 2014||The Invention Science Fund I, Llc||Frozen compositions and array devices thereof|
|US8784385||15 Sep 2009||22 Jul 2014||The Invention Science Fund I, Llc||Frozen piercing implements and methods for piercing a substrate|
|US8788211||31 Oct 2008||22 Jul 2014||The Invention Science Fund I, Llc||Method and system for comparing tissue ablation or abrasion data to data related to administration of a frozen particle composition|
|US8788212||31 Mar 2009||22 Jul 2014||The Invention Science Fund I, Llc||Compositions and methods for biological remodeling with frozen particle compositions|
|US8793075||31 Oct 2008||29 Jul 2014||The Invention Science Fund I, Llc||Compositions and methods for therapeutic delivery with frozen particles|
|US8798932||15 Sep 2009||5 Aug 2014||The Invention Science Fund I, Llc||Frozen compositions and methods for piercing a substrate|
|US8798933||15 Sep 2009||5 Aug 2014||The Invention Science Fund I, Llc||Frozen compositions and methods for piercing a substrate|
|US8858912||15 Sep 2009||14 Oct 2014||The Invention Science Fund I, Llc||Frozen compositions and methods for piercing a substrate|
|US8912168||5 Sep 2013||16 Dec 2014||Xin Ji||Modified starch material of biocompatible hemostasis|
|US8920364||28 Feb 2013||30 Dec 2014||Medtronic Xomed, Inc.||Biomaterial delivery device|
|US9040087||15 Sep 2009||26 May 2015||The Invention Science Fund I, Llc||Frozen compositions and methods for piercing a substrate|
|US9044546||22 Aug 2013||2 Jun 2015||Powder Pharmaceuticals Incorporated||Particle cassettes and processes therefor|
|US9050070||26 Feb 2009||9 Jun 2015||The Invention Science Fund I, Llc||Compositions and methods for surface abrasion with frozen particles|
|US9050251||20 Mar 2009||9 Jun 2015||The Invention Science Fund I, Llc||Compositions and methods for delivery of frozen particle adhesives|
|US9050317||31 Oct 2008||9 Jun 2015||The Invention Science Fund I, Llc||Compositions and methods for therapeutic delivery with frozen particles|
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|US9358338||28 Apr 2015||7 Jun 2016||Powder Pharmaceuticals Incorporated||Particle cassettes and processes therefor|
|US20100112068 *||31 Mar 2009||6 May 2010||Searete Llc, A Limited Liability Corporation Of The State Of Delaware||Compositions and methods for biological remodeling with frozen particle compositions|
|US20100121262 *||4 Nov 2009||13 May 2010||Lee's Pharmaceutical (Hk), Ltd.||Particle cassettes and processes therefor|
|US20100143243 *||15 Sep 2009||10 Jun 2010||Searete Llc, A Limited Liability Corporation Of The State Of Delware||Frozen compositions and methods for piercing a substrate|
|US20100185174 *||30 Oct 2009||22 Jul 2010||Searete Llc, A Limited Liability Corporation Of The State Of Delaware||Systems, devices, and methods for making or administering frozen particles|
|US20110066132 *||17 Mar 2011||Xin Ji||Internal dry powder delivery system and method thereof|
|US20120107765 *||18 Jun 2010||3 May 2012||Koninklijke Philips Electronics N.V.||Atomized liquid oral cleaning appliance|
|US20140215842 *||13 Dec 2013||7 Aug 2014||Flash Rockwell Technologies, Llc||Non-Thermal Drying Systems with Vacuum Throttle Flash Generators and Processing Vessels|
|US20140308625 *||19 Dec 2012||16 Oct 2014||Koninklijke Philips N.V.||Device for delivery of a tooth whitening agent|
|USRE43824||11 Jan 2002||20 Nov 2012||Powder Pharmaceuticals Inc.||Needleless syringe|
|U.S. Classification||604/68, 604/72|
|International Classification||A61M5/30, A61M5/20|
|Cooperative Classification||A61M2005/005, A61M5/3015, A61M5/2053, A61M5/3007|
|24 Dec 2003||AS||Assignment|
Owner name: POWDERJECT RESEARCH LIMITED, GREAT BRITAIN
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SHELDRAKE, COLIN DAVID;COSTIGAN, GEORGE;BELLHOUSE, BRIANJOHN;REEL/FRAME:014827/0807;SIGNING DATES FROM 20031216 TO 20031218
|15 Jun 2010||CC||Certificate of correction|
|11 Aug 2010||AS||Assignment|
Owner name: ANESIVA, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:POWDERJECT RESEARCH LIMITED;REEL/FRAME:024822/0758
Effective date: 20091130
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ANESIVA, INC.;REEL/FRAME:024822/0871
Owner name: POWDER PHARMACEUTICALS INC., HONG KONG
Effective date: 20091203
|22 Nov 2011||RF||Reissue application filed|
Effective date: 20110331